Inflammatory lung disorders are typically of a chronic nature, they increase morbidity and may, ultimately, cause death. They include a range of diseases including, but not limited to, asthma, bronchitis and chronic obstructive pulmonary disease (COPD).
Of this group, asthma affects 1 in 12 of the population in the UK, with 5.4 million people currently receiving treatment. The UK has one of the highest prevalence of asthma in young adults in Europe and the numbers of children reporting asthmatic symptoms has risen six-fold over the last 30 years. It is estimated that 3 people die each day as a result of asthma. Asthma costs the NHS approximately £1 BN per year and at least one million working days are lost each year due to asthma.
Moreover, while current asthma pharmacotherapy is adequate to control the disease for many patients, a significant number of them do not respond well and continue to suffer from symptoms and from unwanted effects of existing therapies. Indeed, a substantial proportion of the cost of asthma treatment is directed at patients (approximately 10% of the total) whose symptoms are poorly controlled despite aggressive treatment with current therapies.
Thus, there is an urgent need for a better understanding of the pathogenic process in order that new therapeutic agents can be developed which target newly identified molecular mechanisms to improve patients' quality of life and to reduce asthma management costs.
Asthma is characterised by excessive airways narrowing due to bronchospasm, bronchial hyper-responsiveness (BHR), inflammation and airways remodelling. BHR, the phenomenon whereby asthmatic airway smooth muscle is hyper-reactive to a wide variety of specific and non-specific stimuli, is a fundamental pathophysiological feature. Although a comprehensive picture of the major characteristics of BHR exists, the underlying causes are still poorly understood. In asthmatics, plasma concentrations of polycations are markedly increased. Indeed, polycations, such as poly-arginine, poly-L-lysine, spermine and eosinophil-derived cationic proteins (ECPs) are markers for asthma severity, and there is evidence that they may contribute directly to the pathogenesis of the disease. Associations between increases in polycations in the asthmatic airway mucosa and BHR/airway remodelling in asthma have long been apparent and have been ascribed to their positive charge, but the precise molecular mechanisms linking raised polycations to BHR remain unexplained.
However, herein we show for the first time that the extracellular calcium/cation-sensing receptor (CaSR) provides a link between polycations and BHR/airway remodelling in asthma, and so is a key, novel molecular target for asthma treatment.
The CaSR is a pleiotropic, G protein-coupled receptor which plays a fundamental role in mineral ion metabolism (see (1) for recent review). While extracellular Ca2+ (Ca2+o) is the physiological ligand for this receptor, CaSR is also activated by many polycations including those implicated in asthma, such as, but not limited to, poly-L-arginine, poly-L-lysine and spermine (2). CaSR signalling results primarily in mobilisation of intracellular Ca2+ (Ca2+i) (1), which in the case of airway smooth muscle cells in turn regulates the global contractile response of the cells to a contractile stimulus but also influences the lifespan, migratory and secretory properties of these cells.
We show herein that the CaSR is expressed in human and mouse airway smooth muscle (ASM) cells, where it is activated by polycations, including ECPs, and that these effects are blocked by antagonists such as, but not limited to, negative allosteric modulators of the CaSR, termed “calcilytics”. Calcilytics prevent bronchoconstriction induced by polycations and act as mild bronchodilators in mouse intralobular bronchi. Furthermore, we show that, nebulised calcilytics alleviate the BHR induced by polycations or following ovalbumin sensitisation (a common experimental model of asthma) in conscious mice in vivo. Finally, calcilytics reduce inflammatory cell infiltration in two mammalian species of asthma and COPD; the ovalbumin-sensitised/ovalbumin challenged mouse and the lipopolysaccharide-treated guinea pig. Together these data show that the CaSR represents a novel target for inflammatory lung disorders, specifically asthma and COPD.
Notably, calcilytics are safe for human use and already in phase II clinical trials for the treatment of osteoporosis.
Based on the current studies, because of their ability to reduce polycation-induced airway hyper-reactivity and by acting as bronchodilators, we herein teach that locally delivered calcilytics can be used to supress or reverse the functional abnormalities of airway smooth muscle in inflammatory lung disorders and, in particular, asthma and COPD.